Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
  • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/452—Piperidinium derivatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to novel quinuclidines derivatives, pharmaceutical compositions, and use thereof in treating muscarinic acetylcholine receptor mediated diseases of the respiratory tract.
• mAChRs Muscarinic acetylcholine receptors
• Muscarinic acetylcholine receptors are widely distributed in vertebrate organs where they mediate many of the vital functions. Muscarinic receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, M3 mAChRs mediate contractile responses. For review, please see Caulfield (1993
• mAChRs have been localized to smooth muscle in the trachea and bronchi, the submucosal glands, and the parasympathetic ganglia. Muscarinic receptor density is greatest in parasympathetic ganglia and then decreases in density from the submucosal glands to tracheal and then bronchial smooth muscle. Muscarinic receptors are nearly absent from the alveoli.
• M 3 mAChRs located on airway smooth muscle, mediate muscle contraction. Stimulation of M 3 mAChRs activates the enzyme phospholipase C via binding of the stimulatory G protein Gq/11 (Gs), leading to liberation of phosphatidyl inositol-4,5-bisphosphate, resulting in phosphorylation of contractile proteins.
• Gq/11 stimulatory G protein Gq/11
• M 3 mAChRs are also found on pulmonary submucosal glands. Stimulation of this population of M 3 mAChRs results in mucus secretion.
• M 2 mAChRs make up approximately 50-80% of the cholinergic receptor population on airway smooth muscles. Although the precise function is still unknown, they inhibit catecholaminergic relaxation of airway smooth muscle via inhibition of cAMP generation.
• Neuronal M 2 mAChRs are located on postganglionic parasympathetic nerves. Under normal physiologic conditions, neuronal M 2 mAChRs provide tight control of acetylcholine release from parasympathetic nerves. Inhibitory M 2 mAChRs have also been demonstrated on sympathetic nerves in the lungs of some species. These receptors inhibit release of noradrenaline, thus decreasing sympathetic input to the lungs.
• Mi mAChRs are found in the pulmonary parasympathetic ganglia where they function to enhance neurotransmission. These receptors have also been localized to the peripheral lung parenchyma, however their function in the parenchyma is unknown.
• Muscarinic acetylcholine receptor dysfunction in the lungs has been noted in a variety of different pathophysiological states.
• COPD chronic obstructive pulmonary disease
• inflammatory conditions lead to loss of inhibitory M2 muscarinic acetylcholine autoreceptor function on parasympathetic nerves supplying the pulmonary smooth muscle, causing increased acetylcholine release following vagal nerve stimulation (Fryer et al. 1999 Life Sci 64 (6-7) 449-55).
• This mAChR dysfunction results in airway hyperreactivity and hyperresponsiveness mediated by increased stimulation of M3 mAChRs.
• COPD ulcerative colitis
• COPD chronic bronchitis, chronic bronchiolitis and emphysema
• Smoking is the major risk factor for the development of COPD; nearly 50 million people in the U.S. alone smoke cigarettes, and an estimated 3,000 people take up the habit daily.
• COPD is expected to rank among the top five as a world-wide health burden by the year 2020.
• Inhaled anti-cholinergic therapy is currently considered the "gold standard" as first line therapy for COPD (Pauwels et al. 2001 Am. J. Respir. Crit. Care Med. 163:1256-1276).
• relatively few anti-cholinergic compounds are available for use in the clinic for pulmonary indications.
• Combivent ⁇ in combination with albuterol is currently the only inhaled anti- cholinergic marketed for the treatment of airway hyperreactive diseases. While this compound is a potent anti-muscarinic agent, it is short acting, and thus must be administered as many as four times daily in order to provide relief for the COPD patient, hi Europe and Asia, the long-acting anti-cholinergic Tiotropium Bromide
• This invention provides for a method of treating a muscarinic acetylcholine receptor (mAChR) mediated disease, wherein acetylcholine binds to an mAChR and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• This invention also relates to a method of inhibiting the binding of acetylcholine to its receptors in a mammal in need thereof which comprises administering to aforementioned mammal an effective amount of a compound of Formula (I).
• the present invention also provides for the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutical carrier or diluent.
• Compounds of Formula (I) useful in the present invention are represented by the structure:
• Rl is selected from the group consisting of Cl-15 alkyl, halosubstituted Cl-15 alkyl, Cl-15 alkyl cycloalkyl, cycloalkyl, C2-15 alkenyl, hydroxy substituted Cl-15 alkyl, Cl-15 alkyl aryl, Cl-15 alkyl heteroaryl, (CR7R7)qNRaRa, (CR7R7)qNC(O)Ra, (CR7R7)qC(O)NRaRa, (CR7R7)qC(O)Ra, (CR7R7)qOC (O)Ra, (CR7R7)qNRaC(O)NRaRa, (CR7R7)qORc and (CR7R7)qNS(O) 2 Ra
• Rl is selected from the group consisting of:
• Rl is selected from the group consisting of:
• R2 and R3 are independently selected from the group consisting of aryl, Cl-4 alkyl aryl, heteroaryl, Cl-4 alkyl heteroaryl, heterocyclic and a Cl-4 alkyl heterocyclic moiety, all of which moieties may be optionally substituted;
• Ra is selected from the group consisting of hydrogen, Cl-15 alkyl, Cl-15 alkoxy, aryl, Cl-15 alkyl aryl, heteroaryl, Cl-15 alkyl heteroaryl, heterocyclic and a Cl-15 alkyl heterocyclic moiety, all of which moieties may be optionally substituted;
• Re is selected from the group consisting of hydrogen, Cl-15 alkyl, Cl-15 alkoxy, heterocyclic and a Cl-15 alkyl heterocyclic moiety, all of which moieties may be optionally substituted;
• R4 and R5 are independently selected from the group consisting of hydrogen, halogen, Cl-4 alkyl, aryl, Cl-4 alkyl aryl, cyano, nitro, (CR7R7)pORb, (CR7R7)pNRbRb, or R4 and R5 together may form a 5 to 6 membered saturated or unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroalkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;
• R6 is selected from the group consisting of hydrogen, Cl-4 alkyl
• X, Y, Z and W are independently selected from the group consisting of hydrogen, Cl-4 alkyl;
• V is selected from the group consisting of CH 2 , O, S, andNRb;
• M is O or CH 2
• Rb is selected from the group consisting of hydrogen, Cl-4 alkyl, aryl and Cl-4 alkyl aryl;
• R7 is selected from the group consisting of hydrogen, Cl-4 alkyl, halosubstituted Cl-4 alkyl, and hydroxysubstituted Cl-4 alkyl;
• X- is a physiologically acceptable anion, such as chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate.
• This invention related to novel bi-aryl 8-azoniabicyclo[3.2.1]octane compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating mAChR mediated diseases.
• the compound is of formula
• Rl is selected from the group consisting of Cl-10 alkyl, halosubstituted Cl-10 alkyl, Cl-10 alkyl aryl, Cl-10 alkyl cycloalkyl, cycloalkyl, hydroxy substituted Cl-10 alkyl, C2-10 alkenyl, (CR7R7)qORc; (CR7R7)qOC (O)Ra and (CR7R7)qNS(O) 2 Ra;
• Rl is selected from the group consisting of:
• R2 and R3 are, independently, selected from the group consisting of:
• F, G, H, K and L are independently selected from the group consisting of hydrogen, halogen, Cl-4 alkyl, halosubstituted Cl-4 alkyl, hydoxysubstituted Cl-4 alkyl, and Cl- 4 alkoxy;
• Ra is selected from the group consisting of hydrogen, Cl-10 alkyl, Cl-10 alkoxy, aryl and heteroaryl, all of which moieties may be optionally substituted;
• Re is selected from the group consisting of hydrogen, Cl-5 alkyl, Cl-5 alkoxy, all of which moieties may be optionally substituted;
• R4 and R5 are independently selected from the group consisting of hydrogen, halogen,
• Cl-4 alkyl, aryl, Cl-4 alkyl aryl, cyano, nitro, (CR7R7)pORb, (CR7R7)pNRbRb, or R4 and R5 together may form a 5 to 6 membered saturated or unsaturated ring;
• V is O, or CH 2;
• R6 is selected from the group consisting of hydrogen, Cl-4 alkyl
• M is O or CH 2
• Rb is selected from the group consisting of hydrogen, Cl-4 alkyl, and aryl Cl-4 alkyl
• R7 is selected from the group consisting of hydrogen, and Cl-4 alkyl
• X- is a physiologically acceptable anion, such as chloride, bromide, iodide, hydroxide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate. All of the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted as defined herein below. For use herein the .
• the aryl, heteroaryl, and heterocyclic containing moieties refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings.
• the term “moieties” and “rings” may be interchangeably used throughout.
• halogen such as fluorine, chlorine, bromine or iodine
• hydroxy hydroxy substituted C ⁇ _ioalkyl
• Cl-io alkoxy such as methoxy or ethoxy
• S(O) m Cl- 10 alkyl, wherein m' is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl
• halo all halogens, that is chloro, fluoro, bromo and iodo.
• C _ ⁇ oalkyl or “alkyl” - both straight and branched chain moieties of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, ra-propyl, wo-propyl, rc-butyl, sec-butyl, iso-butyl, fert-butyl, «-pentyl and the like.
• cycloalkyl is used herein to mean cyclic moiety, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
• alkenyl is used herein at all occurrences to mean straight or branched chain moiety of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2- butenyl and the like.
• aryl - phenyl and naphthyl; • “heteroaryl” (on its own or in any combination, such as “heteroaryloxy", or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, triazole, imidazole, indole or benzimidazole.
• heterocyclic (on its own or in any combination, such as “heterocyclicalkyl”) - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine, or imidazolidine.
• sulfur may be optionally oxidized to the sulfone or the sulfoxide.
• arylalkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean
• Illustrative compounds of Formula (I) include: l-(2- ⁇ [(3-fluorophenyl)methyl]oxy ⁇ ethyl)-4-[hydroxy(diphenyl)methyl]-l- azoniabicyclo[2.2.2]octane bromide
• the preferred compounds useful in the present invention include: 1 -(2- ⁇ [(3 -fluorophenyl)methyl] oxy ⁇ ethyl)-4- [hydroxy (diphenyl)methyl] - 1 - azoniabicyclo [2.2.2] octane bromide
• the more preferred compounds useful in the present invention include:
• the most preferred compounds useful in the present invention include:
• the compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below.
• the synthesis provided in this Scheme is applicable for producing compounds of Formula (I) having a variety of different Rl, R2 and R3 groups which are reacted, employing substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. While the Schemes are shown with compounds only of Formula (I), this is merely for illustration purpose only.
• the desired compounds of Formula (I) can be prepared in four synthetic steps from the commercially available ethyl 4-piperidinecarboxylate precursor 1.
• Compound 1 is reacted with l-bromo-2-chloroethane following standard alkylation procedures well known in the art such as potassium carbonate in acetone followed by reaction of the intermediate with lithium diisopropylamide in an aprotic solvent such as tetrahydrofurann to give the quinuclidine intermediate 2.
• Reagents and conditions a) l-bromo-2-chloroethane, K 2 CO 3 , acetone; b) LDA, THF; c) R 2 M then R 3 M, THF; d) R1X, ACN, CHC1 3 .
• Example 3 Preparation of 4-[hydroxy(diphenyI)methyl]-l-[2-(phenyloxy)ethyl]- l-azoniabicyclo[2.2.2]octane bromide.
• Example 6 Preparation of 4-[hydroxy(diphenyl)methyl]-l-[3-(phenyloxy)propyl]- l-azoniabicycIo[2.2.2]octane bromide.
• Example 7 Preparation of 4-[hydroxy(diphenyl)methyl]-l-[4-(phenyloxy)butyl]- 1-azoniabicy clo [2.2.2] octane bromide.
• Example 10 Preparation of 4-[hydroxy(diphenyl)methyl]-l- ⁇ 3- [(phenylmethy ⁇ )oxy]propyl ⁇ -l-azoniabicyclo[2.2.2]octane bromide.
• Example 11 Preparation of l- ⁇ 2-[(2,4-dibromophenyl)oxy]ethyl ⁇ -4- [hydroxy(diphenyl)methyl]-l ⁇ azoniabicyclo[2.2.2]octane bromide.
• Example 13 Preparation of 4-[hydroxy(dipheny ⁇ )methyl]-l-(tetrahydro-2 J fiT- pyran-2-ylmethyI)-l ⁇ azoniabicyclo [2.2.2] octane bromide.
• Example 14 Preparation of l-(l,3-dioxolan-2-ylmethyl)-4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 15 Preparation of l-ethyI-4-[hydroxy(diphenyI)methyl]-l- azoniabicyclo [2.2.2] octane bromide.
• Example 17 Preparation of 4-[hydroxy(diphenyl)methyl]-l-(4-penten-l-yI)-l- azoniabicyclo [2.2.2] octane bromide.
• Example 18 Preparation of 4-[hydroxy(diphenyl)methyl]-l-(2-hydroxyethyl)-l- azoniabicyclo [2.2.2] octane bromide.
• Example 19 Preparation of l-(5-hexen-l-yl)-4-[hydroxy(diphenyl)methyl]-l- azoniabicy clo [2.2.2] octane bromide.
• Example 21 Preparation of 4-[hydroxy(diphenyl)methyl]-l-[2-(methyloxy)ethyl]- l-azoniabicycIo[2.2.2]octane bromide.
• Example 22 Preparation of l-[2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)ethyl]-4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 23 Preparation of l-[3-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)propyl]- 4 ⁇ [hydroxy(diphenyl)methyl]-l-azoniabicycIo[2.2.2]oetane bromide.
• Example 25 Preparation of 4-[hydroxy(diphenyI)methyl]-l-(2- ⁇ [2- (methyIoxy)ethyl]oxy ⁇ ethyl)-l-azoniabicyclo[2.2.2]octane bromide.
• Example 26 Preparation of l-[4-(ethyloxy)-4-oxobutyl]-4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 27 Preparation of l-azabicycIo[2.2.2]oct-4-yl(di-2-thienyI)methanol.
• Example 28 Preparation of 4-[hydroxy(di-2-thienyl)methyl]-l-[2- (phenyloxy)ethyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 29 Preparation of 4-[hydroxy(di-2-thienyl)methyl]-l-[3- (phenyloxy)propyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 30 Preparation of 4-[hydroxy(di-2-thienyI)methyl]-l-(2-phenyIethyI)-l- azoniabic clo [2.2.2] octane bromide.
• Example 32 Preparation of l-butyl-4-[hydroxy(di ⁇ 3-thienyI)methyl]-l- azoniabicyclo [2.2.2] octane bromide.
• Example 33 Preparation of l-azabicyclo[2.2.2]oct-4-yl(di-3-thienyl)methanol.
• Example 34 Preparation of 4-[hydroxy(di-3-thienyl)methyl]-l-[2- (phenyloxy)ethyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 35 Preparation of 4-[hydroxy(di-3-thienyl)methyl] ⁇ l-[3 ⁇ (phenyloxy)propyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 36 Preparation of l ⁇ butyl-4-[hydroxy(diphenyl)methyl]-l- azoniabic clo [2.2.2] octane bromide.
• Example 37 Preparation of l-hexyl-4-[hydroxy(diphenyl)methyl]-l- azoniabicy clo [2.2.2] octane bromide.
• Example 38 Preparation of 4-[hydroxy(dipheny ⁇ )methyl]-l-propyl-l- azoniabicyclo [2.2.2] octane bromide.
• Example 39 Preparation of 4-[hydroxy(diphenyl)methyl]-l-(3- ⁇ [2- (methyloxy)phenyl] oxy ⁇ propyl)-l-azoniabicyclo [2.2.2] octane bromide.
• Example 40 Preparation of 4-[hydroxy(diphenyl)methyI]-l- ⁇ 3-[(2- hydroxyphenyl)oxy]propyl ⁇ -l-azoniabicyclo[2.2.2]octane bromide.
• Example 42 Preparation of l- ⁇ 3-[(3-chlorophenyl)oxy]propyl ⁇ -4- [hydroxy(dipheny ⁇ )methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 43 Preparation of l ⁇ 3-[(4-bromophenyl)oxy]propyl ⁇ -4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 44 Preparation of 4-[hydroxy(diphenyl)methyl]-l- ⁇ 3-[(4- nitropheny ⁇ )oxy]propyl ⁇ -l-azoniabicyclo[2.2.2]octane bromide.
• Example 45 Preparation of 4-[hydroxy(diphenyl)methyl]-l-[3-( ⁇ 2- [(phenylmethyl)oxy]phenyl ⁇ oxy)propyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 46 Preparation of l- ⁇ 3-[(2-bromophenyl)oxy]propyl ⁇ -4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 47 Preparation of 4-[hydroxy(diphenyl)methyl]-l-[3-( ⁇ 4- [(phenylmethyl)oxy]phenyl ⁇ oxy)propyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 48 Preparation of 4-[hydroxy(diphenyl)methyl]-l-[3- (methyloxy)propyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 49 Preparation of 4-[hydroxy(dipheny ⁇ )methyl]-l-(2-propen-l-yl)-l- azoniabicyclo [2.2.2] octane bromide.
• Example 50 Preparation of 4-[hydroxy(diphenyl)methyl]-l-(3- ⁇ [4- (methyloxy)phenyl]oxy ⁇ propyl)-l-azoniabicyclo[2.2.2]octane bromide. Following the general procedure outlined in Example 3, l-azabicyclo[2.2.2]oct-4- yl(diphenyl)methanol (0.0483 g, 0.164 mmol) and l-[(3-bromopropyl)oxy]-4- (methyloxy)benzene (0.052 g, 0.21 mmol) in 2 CH 3 CN / 3 CHC1 3 (4.0 mL) were reacted to give the desired product (0.0687 g, 77.5%). EI-MS m/z 458(M + ) Rt (2.03 • min).
• Example 51 Preparation of [l-(2-aminoethy ⁇ )-l-azoniabicyclo[2.2.2]oct-4- yl](dipheny ⁇ )n ⁇ ethanoIate trifluoroacetate.
• l-[2-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)ethyl]-4- [hydroxy(diphenyl)methyl]-l -azoniabicy clo [2.2.2] octane bromide (0.078g, 0.142 mmol) in EtOH (4.0 mL) was added hydrazine (0.25 mL, 7.96 mmol).
• Example 54 Preparation of 4-(hydroxy ⁇ bis[3-(methyloxy)phenyl] ⁇ methyl)-l-[3- (phenyloxy)propyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 55 Preparation of 4-(hydroxy ⁇ bis[3-(methyIoxy)phenyI] ⁇ methy ⁇ )-l- ⁇ 2- [(phenylmethyl)oxy] ethyl ⁇ -l-azoniabic clo [2.2.2] octane bromide.
• Example 56 Preparation of 4-(hydroxy ⁇ bis[4-(methyloxy)phenyl] ⁇ methyl)-l-[3- (phenyloxy)propyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 57 Preparation of 4-(hydroxy ⁇ bis[4-(methyIoxy)phenyl] ⁇ methyI)-l- ⁇ 2- [(phenylmethyl)oxy]ethyl ⁇ -l-azoniabicyclo[2.2.2]octane bromide.
• Example 58 Preparation of 4-[bis(3-fluorophenyl)(hydroxy)methyl]-l-[3- (phenyloxy)propyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 59 Preparation of 4-[bis(3-fluoropheny ⁇ )(hydroxy)methyI]-l- ⁇ 2- [(phenylmethyl)oxy]ethyl ⁇ -l-azoniabicyclo[2.2.2]octane bromide.
• Example 61 Preparation of 4- ⁇ hydroxy[bis(3-methylphenyl)]methyl ⁇ -l- ⁇ 2- [(phenylmethyl)oxy]ethyl ⁇ -l ⁇ azoniabicyclo[2.2.2]octane bromide.
• Example 63 Preparation of 4- ⁇ hydroxy[bis(4-methylpheny ⁇ )]methyI ⁇ -l- ⁇ 2- [(phenylmethyl)oxy]ethyl ⁇ -l-azoniabicyclo[2.2.2] octane bromide.
• Example 64 Preparation of 4-[hydroxy(di-2-naphthalenyl)methyl]-l-[3- (phenyloxy)propyl] -1-azoniabicy clo [2.2.2] octane bromide.
• Example 65 Preparation of 4-[hydroxy(di-2-naphthalenyl)methyl]-l- ⁇ 2- [(phenylmethyl)oxy]ethyl ⁇ -l-azoniabicyclo[2.2.2]octane bromide.
• Example 66 Preparation of l- ⁇ 3-[(2-fluorophenyl)oxy]propyl ⁇ -4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• the organic layer was dried through a phase separator and concentrated under vacuum.
• Example 68 Preparation of l- ⁇ 3-[(4-fluoropheny ⁇ )oxy]propyl ⁇ -4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 69 Preparation of l-[3-(3-biphenylyloxy)propyl]-4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 70 Preparation of l-[3-(4-biphenylyloxy)propyl]-4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• the organic layer was dried through a phase separator and concentrated under vacuum.
• Example 72 Preparation of 4-[hydroxy(dipheny ⁇ )methyl]-l- ⁇ 3-[(2- methylphenyl)oxy]propyl ⁇ -l-azoniabicyc!o[2.2.2]octane bromide.
• the organic layer was dried through a phase separator and concentrated under vacuum.
• Example 73 Preparation of l-(3- ⁇ [3-(diethylamino)phenyI]oxy ⁇ propy ⁇ )-4- [hydroxy (diphenyl)methyl] -1-azoniabicyclo [2.2.2] octane bromide.
• Example 74 Preparation of l- ⁇ 3-[(4-cyanophenyl)oxy]propyl ⁇ -4- [hydroxy(dipheny ⁇ )methyl]-l-azoniabicy clo [2.2.2] octane bromide.
• the reaction vessel was wrapped in aluminum foil and stirred at rt for 20 h.
• the reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (160 mg).
• the product was characterized by H NMR (400 MHz) in CDCI3.
• Example 76 Preparation of l-[2-( ⁇ [4-(l,l- dimethylethyl)pheny 1] methyl ⁇ oxy)ethyl] -4- [hydroxy (diphenyl)methyl] -1 - azoniabicyclo [2.2.2] octane bromide.
• Example 78 Preparation of l-(2- ⁇ [(4-chlorophenyl)methyl]oxy ⁇ ethyI)-4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 79 Preparation of l-(2- ⁇ [(4-bromophenyl)methyI]oxy ⁇ ethyl)-4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• Example 80 Preparation of l-(2- ⁇ [(4-cyanophenyl)methyl]oxy ⁇ ethyl)-4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• the aqueous layer was extracted with EtOAc (l x l mL), and the combined organic layers were concentrated.
• the crude product was purified on a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: 10% EtOAc/hexanes (fractions 1,2), 30% EtOAc/hexanes (fractions 3,4), 50% EtOAc/hexanes (fractions 5-7), and 75% EtOAc/hexanes (fraction 8) to give the title compound (95 mg, 36%).
• the product was characterized by *H NMR (400 MHz) in CDCI3.
• Example 81 Preparation of 4-[hydroxy(diphenyl)methyl]-l- ⁇ 2-[(2- naphthalenylmethyl)oxy]ethyl ⁇ -l-azoniabicyclo[2.2.2]octane bromide.
• the aqueous layer was extracted with EtOAc (3 x 1 mL), and the combined orgamc layers were washed with saturated NaCl (1 2 mL), dried (Na2SO4), and concentrated.
• the crude product was purified on a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: 30% EtOAc/hexanes (fractions 1,2), 50% EtOAc/hexanes (fraction 3), and 75% EtOAc/hexanes (fraction 4) to give the title compound (76.2 mg, 25%).
• the product was characterized by H NMR (400 MHz) in CDCI3.
• Example 83 Preparation of 4-[hydroxy(diphenyl)methyl]-l- ⁇ 2-[(l-methyl-l- phenylethyI)oxy]ethyI ⁇ -l-azoniabicyclo[2.2.2]octane bromide.
• a catalytic amount of either j>-toluene sulfonic acid* H 2 O or Bio-Rad SCX resin (analytical grade, 5.1 meq/g, AG 50W-X8) was added to D-methylstyrene (0.5 mL, 3.85 mmol) and ethylene glycol (0.21 mL, 3.85 mmol), and the reaction was stirred at rt for 5 days.
• the reaction mixture was loaded directly onto a SPE cartridge (10 g silica) and eluted with the following 10 mL fractions: 10% EtOAc/hexanes (fractions 1,2), 30% EtOAc/hexanes (fractions 3,4), and 50% EtOAc/hexanes (fractions 5,6) to give the title compound (30.5 mg, 4%) for both conditions.
• the product was characterized by iH NMR (400 MHz) in CDC1 3 .
• Example 84 Preparation of 4-[hydroxy(diphenyl)methyl]-l- ⁇ 2- [(phenylmethyl)oxy]ethyl ⁇ -l-azoniabicyclo[2.2.2]octane bromide.
• Method A l-Azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.020 g, 0.068 mmol) was diluted in CHC1 3 (1.8 mL) and dispensed directly into a 1 dram vial containing 2- bromoethyl phenylmethyl ether (0.022 g, 0.102 mmol). CH 3 CN (1.2 mL) was added; the vial was fitted with a stirring bar and capped. The reaction was stirred and heated at 60 °C for 24 h. The contents of the vial were transferred (after removal of stirring bar) into a polypropylene tube and concenfrated under Nitrogen.
• Example 112 Preparation of l-[2-(l-benzofuran-2-yl)-2-oxoethyl]-4- [hydroxy(diphenyl)methyl]-l-azoniabicyclo[2.2.2]octane bromide.
• l-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.022 g, 0.075 mmol) was diluted in CHC1 3 (1.8 mL) and dispensed directly into a 1 dram vial containing l-(l-benzofuran- 2-yl)-2-bromoethanone (0.027 g, 0.112 mmol).
• inhibitory effects of compounds at the M3 mAChR of the present invention are determined by the following in vitro and in vivo functional assays:
• mice were pre-treated with 50 ⁇ l of compound (0.003-10 ⁇ g/mouse) in 50 ⁇ l of vehicle (10% DMSO) intranasally (i.n.) and were then placed in the plethysmography chamber a given amount of time following drug administration (15 min - 96 h). For potency determination, a dose response to a given drug was performed, and all measurements were taken 15 min following i.n. drug administration. For duration of action determination, measurements were taken anywhere from 15 min to 96 hours following i.n. drug administration. Once in the chamber, the mice were allowed to equilibrate for 10 min before taking a baseline Penh measurement for 5 minutes.
• mice were then challenged with an aerosol of methacholine (10 mg/ml) for 2 minutes. Penh was recorded continuously for 7 min starting at the inception of the methacholine aerosol, and continuing for 5 minutes afterward. Data for each mouse were analyzed and plotted by using GraphPad PRISM software. This experiment allows the determination of duration of activity of the administered compound.
• the present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis.
• Muscarinic Receptor Radioligand Binding Assays Radioligand binding studies using 0.5 nM [ 3 H]-N-methyl scopolamine (NMS) in a SPA format is used to assess binding of muscarinic antagonists to Mi, M 2 , M 3 , V and M 5 muscarinic acetylcholine receptors.
• NMS N-methyl scopolamine
• the SPA beads are pre- incubated with receptor-containing membrane for 30 min at 4 °C. Then 50 mM HEPES and the test compound are added and incubated at room temperature (shaking) for 2 hours. The beads are then spun down and counted using a scintillation counter.
• Tissues were then rinsed every 15 minutes over 1 hour until reaching baseline tone. The preparations were then left for at least 30 minutes before the start of the experiment. Concentration-response curves were obtained by a cumulative addition of carbachol in half-log increments (Van Rossum, 1963, Arch. Int. Pharmacodyn., 143:299), initiated at 1 nM. Each concentration was left in contact with the preparation until the response plateaued before the addition of the subsequent carbachol concentration. Paired tissues were exposed to mAChR antagonist compounds or vehicle for 30 min before carbachol cumulative concentration-response curves were generated. All data is given as mean ⁇ standard error of the mean (s.e.m.) with n being the number of different animals. For superfusion (duration of action) studies, the tissues were continuously superfused with Krebs-Henseleit solution at 2 ml/min for the duration of the experiment. Stock solutions of agonist and antagonist were infused (0.02 ml/min) via
• Isoproterenol exposure was halted and the carbachol-induced tension allowed to recover.
• Muscarinic receptor antagonists infused at a single concentration per tissue until a sustained level of inhibition was attained. The compound was then removed and, once again, the carbachol-induced tension was allowed to recover. The following parameters were determined for each concentration of antagonist, and expressed as the mean ⁇ S.E.M. for n individual animals. Inhibition of the carbachol-induced contraction was expressed as a percent of the reference response (isoproterenol) and the time required to reach one-half of this relaxation was measured (onset of response). The tension recovery following removal of the compound was determined as was the time required to reach one-half of the maximum tension recovery (offset of response).
• Antagonist concentration-response curves were obtained by plotting the maximal relaxation data at 0, 60 and 180-min following antagonist withdrawal. Recovery, termed shift, was calculated from the ratio of the 0-min inhibition curve IC50 and the concentration of compound yielding a similar tension recovery at 60 and
• the present invention further provides a pharmaceutical formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative (e.g., salts and esters) thereof, and a pharmaceutically acceptable carrier or excipient, and optionally one or more other therapeutic ingredients.
• active ingredient means a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
• Compounds of formula (I) will be administered via inhalation via the mouth or nose.
• Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator.
• Powder blend formulations generally contain a powder mix for inhalation of the compound of the invention and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di- or poly-saccharides (e.g., lactose or starch), organic or inorganic salts (e.g., calcium chloride, calcium phosphate or sodium chloride), polyalcohols (e.g., mannitol), or mixtures thereof, alternatively with one or more additional materials, such additives included in the blend formulation to improve chemical and/or physical stability or performance of the formulation, as discussed below, or mixtures thereof.
• a suitable powder base such as mono-, di- or poly-saccharides (e.g., lactose or starch),
• Each capsule or cartridge may generally contain between 20 ⁇ g- lOmg of the compound of formula (I) optionally in combination with another therapeutically active ingredient.
• the compound of the invention may be presented without excipients, or may be formed into particles comprising the compound, optionally other therapeutically active materials, and excipient materials, such as by co-precipitation or coating.
• the medicament dispenser is of a type selected from the group consisting of a reservoir dry powder inhaler (RDPI), a multi-dose dry powder inhaler (MDPI), and a metered dose inhaler (MDI).
• reservoir dry powder inhaler By reservoir dry powder inhaler (RDPI) it is meant as an inhaler having a reservoir form pack suitable for comprising multiple (un-metered doses) of medicament in dry powder form and including means for metering medicament dose from the reservoir to a delivery position.
• the metering means may for example comprise a metering cup or perforated plate, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation.
• multi-dose dry powder inhaler MDPI
• the carrier has a blister pack form, but it could also, for example, comprise a capsule-based pack form or a carrier onto which medicament has been applied by any suitable process including printing, painting and vacuum occlusion.
• the formulation can be pre-metered (eg as in Diskus, see GB 2242134 or
• the Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a compound of formula (I) preferably combined with lactose.
• the strip is sufficiently flexible to be wound into a roll.
• the lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. Also, preferably the hermetic seal between the base and lid sheets extends over their whole width.
• the lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.
• the multi-dose pack is a blister pack comprising multiple blisters for containment of medicament in diy powder form. The blisters are typically arranged in regular fashion for ease of release of medicament therefrom.
• the multi-dose blister pack comprises plural blisters arranged in generally circular fashion on a disk-form blister pack.
• the multi-dose blister pack is elongate in form, for example comprising a strip or a tape.
• the multi-dose blister pack is defined between two members peelably secured to one another.
• US Patents Nos. 5,860,419, 5,873,360 and 5,590,645 describe medicament packs of this general type.
• the device is usually provided with an opening station comprising peeling means for peeling the members apart to access each medicament dose.
• the device is adapted for use where the peelable members are elongate sheets which define a plurality of medicament containers spaced along the length thereof, the device being provided with indexing means for indexing each container in turn.
• the device is adapted for use where one of the sheets is a base sheet having a plurality of pockets therein, and the other of the sheets is a lid sheet, each pocket and the adjacent part of the lid sheet defining a respective one of the containers, the device comprising driving means for pulling the lid sheet and base sheet apart at the opening station.
• metered dose inhaler it is meant a medicament dispenser suitable for dispensing medicament in aerosol form, wherein the medicament is comprised in an aerosol container suitable for containing a propellant-based aerosol medicament formulation.
• the aerosol container is typically provided with a metering valve, for example a slide valve, for release of the aerosol form medicament formulation to the patient.
• the aerosol container is generally designed to deliver a predetermined dose of medicament upon each actuation by means of the valve, which can be opened either by depressing the valve while the container is held stationary or by depressing the container while the valve is held stationary.
• Spray compositions for topical delivery to the lung by inhalation may for example be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.
• Aerosol compositions suitable for inhalation can be either a suspension or a solution and generally contain the compound of formula (I) optionally in combination with another therapeutically active ingredient and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g. dichlorodifluoromethane, frichlorofluoromethane, dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3- heptafluoro-n-propane or a mixture thereof.
• a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, e.g. dichlorodifluoromethane, frichlorofluoromethane, dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane
• the aerosol composition may be excipient free or may optionally contain additional formulation excipients well known in the art such as surfactants eg oleic acid or lecithin and cosolvents eg ethanol.
• Pressurised formulations will generally be retained in a canister (eg an aluminium canister) closed with a valve (eg a metering valve) and fitted into an actuator provided with a mouthpiece.
• Medicaments for administration by inhalation desirably have a controlled particle size.
• the optimum aerodynamic particle size for inhalation into the bronchial system for localized delivery to the lung is usually l-10 ⁇ m, preferably 2-5 ⁇ m.
• the optimum aerodynamic particle size for inhalation into the alveolar region for achieving systemic delivery to the lung is approximately .5-3 ⁇ m, preferably 1-3 ⁇ m. Particles having an aerodynamic size above 20 ⁇ m are generally too large when inhaled to reach the small airways.
• Average aerodynamic particle size of a formulation may measured by, for example cascade impaction. Average geometric particle size may be measured, for example by laser diffraction, optical means.
• the particles of the active ingredient as produced may be size reduced by conventional means eg by controlled crystallization, micronisation or nanomilling . The desired fraction may be separated out by air classification.
• particles of the desired size may be directly produced, for example by spray drying, controlling the spray drying parameters to generate particles of the desired size range.
• the particles will be crystalline, although amorphous material may also be employed where desirable.
• an excipient such as lactose
• the particle size of the excipient will be much greater than the inhaled medicament within the present invention, such that the "coarse" carrier is non-respirable.
• the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a MMD of 60-90 ⁇ m and not less than 15% will have a MMD of less than 15 ⁇ m.
• Additive materials in a dry powder blend in addition to the carrier may be either respirable, i.e., aerodynamically less than 10 microns, or non-respirable, i.e., aerodynamically greater than 10 microns.
• Suitable additive materials which may be employed include amino acids, such as leucine; water soluble or water insoluble, natural or synthetic surfactants, such as lecithin (e.g., soya lecithin) and solid state fatty acids (e.g., lauric, palmitic, and stearic acids) and derivatives thereof (such as salts and esters); phosphatidylcholines; sugar esters.
• Additive materials may also include colorants, taste masking agents (e.g., saccharine), anti-static-agents, lubricants (see, for example, Published PCT Patent Appl. No. WO 87/905213, the teachings of which are incorporated by reference herein), chemical stabilizers, buffers, preservatives, absorption enhancers, and other materials known to those of ordinary skill.
• Sustained release coating materials e.g., stearic acid or polymers, e.g. polyvinyl pyrolidone, polylactic acid
• active material or active material containing particles see, for example, Patent Nos. US 3,634,582, GB 1,230,087, GB
• Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
• Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.
• Preferred unit dosage formulations are those containing an effective dose, as herein before recited, or an appropriate fraction thereof, of the active ingredient.

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